The aim of this prospective multicenter controlled clinical study was to evaluate the efficacy of Emdogain (Biora), an enamel matrix derivative (EMD), when combined with surgical treatment of periodontal angular defects, as compared to surgery alone, for up to 24 months of follow-up. The study was performed at six Italian universities and 11 private practices. Patients with one-, two-, or three-wall angular defects were enrolled if intrabony defect depth (IBD) was 4 mm or more and probing pocket depth (PPD) was at least 6 mm. They were randomly allocated to either test or control groups. The test group was treated by the simplified papilla preservation (SPP) flap plus Emdogain after root conditioning with ethylenediaminetetraacetic acid. The control group was treated by SPP alone. Plaque Index, Gingival Index, PPD, and periodontal attachment level (PAL) at surgical sites were assessed at the presurgical examination (baseline). IBD was measured intraoperatively after debridement. IBD was also evaluated with a computeraided technique, from periapical radiographs. Plaque Index, Gingival Index, PPD, PAL, and IBD were assessed at 12 and 24 months postsurgery. Data were further divided in two subgroups according to baseline IBD (6 mm or less and more than 6 mm). The differences between each follow-up and baseline, and between groups at each follow-up, for the above parameters were evaluated by standard statistical methods. One hundred fifty-three patients were recruited, accounting for 195 intrabony defects: 83 patients (108 defects) and 70 patients (87 defects) were allocated to the test and control groups, respectively. All parameters were improved at both 12 and 24 months, compared to baseline in both groups. In the test group, IBD, PPD, and PAL at 12 months were significantly better than these parameters in the control group. The test subgroup with IBD of more than 6 mm at baseline displayed a better outcome when compared to the 6 mm or less IBD subgroup. No significant adverse events related to the use of Emdogain were reported. The use of EMD as an adjunct to periodontal surgery in the treatment of angular defects significantly enhanced the rate and degree of periodontal regeneration. The control group also displayed significant tissue regeneration, but at a slower rate compared to the Emdogain group. The surgical procedure itself, with its goal of maximum preservation of the regenerative potential of periodontal tissues, proved to be effective in the treatment of periodontal angular defects. Pockets with IBD greater than 6 mm showed major improvement when treated with Emdogain.